Controlled release of therapeutically active agents has become essential in treatments of humans and animals.
In recent years, a number of polymers fabricated into devices as microspheres, microcapsules, liposomes, strands and the like have been developed for this reason. The active agent is incorporated into the interior of the devices and is after administration to the human or animal body slowly released by different mechanisms. U.S. Pat. Nos. 4,079,038, 4,093,709, 4,131,648, 4,138,344, 4,180,646, 4,304,767, 4,946,931 and 5,968,543 disclose various types of polymers that may be used for the controlled delivery of active agents. The fabrication of such devices is in many cases cumbersome, expensive and may also suffer from irreproducibility in the release kinetics. Furthermore, in most cases an organic solvent is used which may have adverse effect on the therapeutic agent and there could also be residual solvent in the device, which in many cases is highly toxic. Moreover the administration of the solution or dispersion containing the devices is not patient friendly, due to the high viscosity of such solutions or dispersions. Further, such devices are not generally useful for the delivery of proteins that usually undergo a loss of activity during their incorporation into the solid polymer.
An important improvement was found in the use of amphiphilic copolymers, especially triblock copolymers BAB with polyethylene glycol) as the central hydrophilic block A and terminal hydrophobic blocks B, with polymer hydroxyl end-groups modified with fatty acid derivatives. Such copolymers may form micelles or thermo-reversible gels in aqueous solutions that may contain at least one therapeutically active agent.
Micelles of the amphiphilic copolymer have a number of useful attributes. For example when micelles having the correct-size are used, which is usually below 40 nm, they will not extravasate in normal vasculature, but are able to extravasate in a tumor that normally has a leaky vasculature. Because of this it is possible to achieve a high concentration of anti-neoplastic agents in the tumor, without incurring excessive toxicity in normal tissues.
In addition to the usefulness as micelles in tumor targeting, micelles also find important applications in the solubilisation of highly water insoluble drugs, since such drugs may be incorporated in the hydrophobic core of the micelle.
The use of micelles in tumor targeting and solubilisation of highly water-insoluble drugs has been extensively described by V. P. Torchilin, “Structure and design of polymeric surfactant-based drug: delivery systems”, J. Controlled Release 73 (2001) 137-172, and by V. P. Torchilin, “Polymeric Immunomicelles: Carriers of choice for targeted delivery of water-insoluble pharmaceuticals”, DrugDelivery Technology, 4 (2004) 30-39.
Micelles based on poly (ethylene glycol) and poly(D,L-lactic acid) have been investigated by J. Lee, “Incorporation and release behavior of hydrophobic drug in functionalized poly(D,L-lactide)-block polyethylene oxide) micelles” J. Controlled Release, 94 (2004) 323-335. Micelles based on poly(ethylene glycol) and poly(β-benzyl-L-aspartate) have been investigated by Katabka, G. Kwon, “Block copolymer micelles for drug delivery: loading and release of doxorubicin” J. Controlled Release, 48 (1997) 195-201. Micelles based on poly(ethylene glycol) and poly(ortho ester) have been described by Toncheva et. al., “Use of block-copolymers of poly(ortho esters) and poly(ethylene glycol) micellar carriers as potential tumor targeting systems”, J. Drug Targeting, 11 (2003) 345-353.
It is also possible for the amphiphilic copolymers of the invention to form a so-called thermo-reversible gel in an aqueous solution. Such a copolymer solution has the peculiar property that at room temperature it is water-soluble and at the body temperature of 37° C. it becomes water-insoluble and forms a gel.
The composition containing the copolymer and the therapeutically active agent may be administered at room temperature as a low viscosity aqueous solution, using a small gauge needle, thus minimizing discomfort for the patient. Once at body temperature the composition will form a well-defined gel that will be localized at the desired site within the body. Further, such materials are also uniquely suited for use with a protein as the therapeutically active agent since the protein is simply dissolved in the same solution that contains the amphiphilic copolymer and the solution is injected, without affecting the properties of the protein.
The therapeutically active agent is slowly released by diffusion, or by a combination of diffusion and erosion, from the micelles or the thermogels made of amphiphilic copolymers. Ultimately, the amphiphilic copolymer has to fall apart into small fragments that can be metabolized or removed from the body.
Thermogels have been extensively investigated. The most extensively investigated thermo gelling polymer is poly(N-isopropyl acrylamide). This polymer is soluble in water below 32° C. and sharply precipitates as the temperature is raised above 32° C. This temperature is known as the lower critical solution temperature, or LCST. Thus, such a polymer could be injected at room temperature as a low viscosity solution using a small bore needle, and once in the tissues, it would precipitate, forming, a well-defined depot. However, such polymers are non-degradable. Such polymers were extensively described by Hoffman, in L. C. Dong et. al., “Thermally reversible hydrogels: III. Immobilization of enzymes for feedback reaction control”, J. Controlled Release, 4 (1986) 223-227.
Thermogels using poly(lactide-co-glycolide) copolymers as the hydrophobic segment and poly(ethylene glycol) as the hydrophilic segment have been extensively investigated and are described in a number of patents and publications: U.S. Pat. Nos. 5,702,717, 6,004,573, 6,117,949, 6,201,072 B1. G. Zentner, J. Controlled Release, 72 (2001) 203-215.
Thermogels using poly(L-lactide-co-ε-caprolactone) copolymers as the hydrophobic segment en poly(ethylene glycol) as the hydrophilic segment have been described in US 2007/0265356. This patent describes end group modification with aliphatic hydrocarbons, in particular C3-C18 aliphatic: hydrocarbons.
In an article published in Angew. Chem. Int. Ed. 2006, 45, p 2232-2235, “A Subtle End-Group Effect on Macroscopic Physical Gelation of Triblock Copolymer Aqueous Solutions”, BAB block copolymers having the blocks PLGA/PEG/PLGA are described. The PEG (i.e. polyethylene glycol A-block) is viewed as the hydrophilic block, the PLGA (i.e. poly(lactic acid-co-glycolic acid B-block) is the hydrophobic block. The article shows that end-groups to the BAB block are important. If the end-group is a hydrogen atom, a soluble system is prepared. If the end-groups are acetate or propionate a thermo reversible gel can be prepared (which gel exists at room temperature, i.e. 25° C.), If the end-groups are butyrate, the modified block copolymer precipitates in a region from 0° C. to 50° C. The extent of esterification (i.e. endcapping in the context of the mentioned article) was higher than 90% for all derivatives.
A disadvantage of triblock copolymers known in the prior art, is that it is difficult to obtain an optimal balance between the polymer's hydrophilicity and hydrophobicity while at least maintaining biodegradability. It is therefore difficult to obtain polymers with a good water solubility and the ability to retain (hydrophobic) therapeutically active agents.
Another disadvantage of triblock copolymers known in the prior art, is that the thermogels formed at body temperature are only able to deliver therapeutically active agents for a few days except very hydrophobic drugs like paclitaxel, due to very fast diffusion of the drug out of the gel mass.
Another disadvantage of triblock copolymers known in the prior art is, that the biodegradability is either very fast (in the order of days) or very slow (in the order of months). This makes these copolymers less suitable for controlled drug release applications in which a treatment in the order of a week or a few weeks, especially when the controlled release is largely determined by the degradation (erosion) of the-gel instead of diffusion of the medicament out of the gel (which may be the case for very hydrophobic drugs)